Summary: Thyroid hormone plays an important regulatory role in the development and function of virtually all organs and its homeostasis is maintained by a highly regulated, multi-step redundant system. The peripheral metabolism of thyroid hormone, by regulating the circulating and intracellular levels of the active hormone T3, represents an important tissue-specific pre-receptor modulator of the hormonal action. The deiodinases are selenoenzymes which convert the pro-hormone T4 into its active hormone T3 or into the metabolically inactive rT3. We previously discovered that a common polymorphism of the type 2 deiodianse gene (Thr92Ala) associates with decreased glucose disposal and, in the presence of a previously described inactivating beta-3 adrenergic receptor polymorphism, with a small but significant increase in body mass index. Interestingly, this polymorphism does not affect indices of insulin resistance in a physically active founder population, the Old Order Amish, suggesting a gene-environment interaction. We speculated that the Thr92Ala polymorphism generates a defective enzyme thus leading to a decrease intracellular conversion of T4 to T3, ultimately leading to reduced energy expenditure and impaired transcription of the insulin-dependent glucose transporter-4, whose gene is thyroid hormone-regulated. During this year we have focused our efforts in developing and implementing a portfolio of clinical protocols aimed to characterize in vivo the role of the peripheral metabolism of thyroid hormone and its role in modulating the energy and glucose metabolism. Specifically, the following protocols have been implemented: 05-DK-0119 Peripheral Thyroid Hormone Conversion and Glucose and Energy Metabolism. This clinical protocol aimed to characterize in vivo the role of the peripheral metabolism of thyroid hormone with respect to glucose and energy metabolism is designed as a double blind, cross over study in which hypothyroid patients are treated either with T4 or T3 and after reaching a stable replacement dose, are admitted to the Metabolic Unit of the Clinical Center for a detailed evaluation of the energy and glucose homeostasis. Presently six patients have completed both phases of the study. 06-DK-0133 Thyroid hormone-induced lipolysis: an in vivo microdialysis study. This clinical protocol is aimed to study, by exploiting the microdialysis technique, the pharmacological action of thyroid hormone on the adipose tissue and to study in vivo the action of the deiodinases. The study is subdivided in four phases. Healthy volunteers are currently recruited and it is expected that the collection of the data will be completed by FY 08. 07-DK-0202 Thyroid hormones homeostasis and energy metabolism changes during exposure to cold temperature in humans. This clinical protocol is aimed to study in vivo, by taking advantage of the newly opened respiratory chamber in the Metabolic Unit of the Clinical Center, the changes of circulating thyroid hormones during exposure to mild changes in environmental temperature. The protocol has recently been approved by the IRB and the recruitment of healthy volunteers is currently ongoing. Thyroid hormones homeostasis and energy metabolism changes during stimulation of endogenously secreted bile acids (BAs) In vitro and animal data indicate that the bile acids activate in a endocrine fashion the conversion of T4 to T3 ultimately leading to an increase in energy expenditure. This translational protocol is aimed to study in healthy volunteers the role of macronutrients and bile acids in the thermic effects of food. The protocol is being submitted to the NIDDK/NIAMS IRB and we expect to begin the recruitment phase within the next three months.